US 5,686,478 AGranted

Endothelin antagonists

AssigneeMerck & Co., Inc.

InventorsWilliam J. Greenlee, Thomas F. Walsh

Life of this patent

Estimating the term…

Abstract

Novel derivatives of the general structural Formula I ##STR1## have endothelin antagonist activity and are therefore useful in treating cardiovascular disorders, such as hypertension, pulmonary hypertension, postischemic renal failure, vasospasm, cerebral and cardiac ischemia, myocardial infarction, endotoxic shock, benign prostatic hyperplasia, complications of diabetes, migraine, bone resorption, and inflammatory diseases, including Raynaud's disease and asthma.

Claims20

Dependent claims

A compound of structural Formula I:

##STR31## or a pharmaceutically acceptable salt thereof, wherein:
R.sup.1 and R.sup.2 on adjacent carbon atoms are joined together to form a heterocyclic oxygen containing ring structure containing the following group --O--C(R.sup.6)(R.sup.6)!--O--;
R.sup.3a and R.sup.3b are independently:
(a) H,
(b) F, Cl, Br, or I,
(c) --NO.sub.2,
(d) --NH.sub.2,
(e) --NH(C.sub.1 -C.sub.4)-alkyl,
(f) --N(C.sub.1 -C.sub.4)-alkyl!.sub.2,
(g) --SO.sub.2 NHR.sup.7,
(h) --CF.sub.3,
(i) (C.sub.1 -C.sub.4)-alkyl,
(j) --OR.sup.7,
(k) --S(O).sub.n --(C.sub.1 -C.sub.4)-alkyl,
(l) --NHCO--(C.sub.1 -C.sub.4)-alkyl,
(m) --NHCO--O(C.sub.1 -C.sub.4)-alkyl,
(n) --CH.sub.2 O--(C.sub.1 -C.sub.4)-alkyl,
(o) --O--(CH.sub.2).sub.x --OR.sup.7,
(p) --CONR.sup.7 R.sup.16, or
(q) --COOR.sup.7 ;
m is:
1 or 2;
n is:
0, 1 or 2;
x is:
2, 3 or 4;
R.sup.6 is:
(a) H,
(b) F, or
(c) (C.sub.1 -C.sub.4)-alkyl unsubstituted or substituted with one of the following substituents:
i) --OH,
ii) --NR.sup.7 R.sup.16,
iii) --COOR.sup.7,
iv) --CONHR.sup.7, or
v) --CONR.sup.7 R.sup.6 ;
R.sup.7 is:
(a) H,
(b) (C.sub.1 -C.sub.6)-alkyl,
(c) phenyl;
(d) benzyl, or
(e) (C.sub.3 -C.sub.7)-cycloalkyl;
R.sup.8 is:
(a) H,
(b) (C.sub.1 -C.sub.6)-alkyl, unsubstituted or substituted with a substituent selected from the group consisting of:
i) -phenyl,
ii) --(C.sub.3 -C.sub.7)-cycloalkyl,
iii) --NR.sup.7 R.sup.16,
iv) -morpholin-4-yl,
v) --OH,
vi) --CO.sub.2 R.sup.7, or
vii) --CON(R.sup.7).sub.2,
(c) phenyl, unsubstituted or substituted with a substituent selected from the group consisting of:
i) (C.sub.1 -C.sub.4)-alkyl
ii) --O--(C.sub.1 -C.sub.4)-alkyl
iii) --CONR.sup.7 R.sup.16,
iv) F, Cl, Br or I,
v) --COOR.sup.7, or
vi) 2,3-, or 3,4-methylenedioxy;
R.sup.9 is:
(a) H,
(b) (C.sub.1 -C.sub.6)-alkyl, unsubstituted or substituted with a substituent selected from the group consisting of:
i) -phenyl,
ii) --(C.sub.3 -C.sub.7)-cycloalkyl,
iii) --NR.sup.7 R.sup.16,
iv) --OH,
v) --O--(C.sub.1 -C.sub.4)-alkyl,
vi) --CF.sub.3,
vii) --COOR.sup.7,
viii) --S(O).sub.n --(C.sub.1 -C.sub.4)-alkyl, or
ix) --CON(R.sup.7).sub.2 ;
(c) (C.sub.3 -C.sub.7)-cycloalkyl,
(d) F, Cl, Br, I,
(e) --COOR.sup.7,
(f) --CON(R.sup.7).sub.2,
(g) -perfluoro-(C.sub.1 -C.sub.4)-alkyl,
(h) --O--(CH.sub.2).sub.x --OR.sup.7, or
(i) --S(O).sub.n --(C.sub.1 -C.sub.4)-alkyl;
R.sup.10 and R.sup.11 are independently:
(a) H,
(b) (C.sub.1 -C.sub.6)-alkyl, unsubstituted or substituted with (C.sub.3 -C.sub.7)-cycloalkyl,
(c) (C.sub.2 -C.sub.6)-alkenyl,
(d) (C.sub.2 -C.sub.6)-alkynyl,
(e) Cl, Br, F, I,
(f) (C.sub.1 -C.sub.6)-alkoxy,
(g) when R.sup.10 and R.sup.11 are on adjacent carbons, they can be joined to form a phenyl ring,
(h) perfluoro-(C.sub.1 -C.sub.6)-alkyl,
(i) (C.sub.3 -C.sub.7)-cycloalkyl, unsubstituted or substituted with (C.sub.1 -C.sub.6)-alkyl,
(j) phenyl,
(k) (C.sub.1 -C.sub.6)-alkyl-S(O).sub.n --(CH.sub.2).sub.n --,
(l) hydroxy-(C.sub.1 -C.sub.6)-alkyl,
(m) --CF.sub.3,
(n) --CO.sub.2 R.sup.7,
(o) --OH,
(p) --NR.sup.7 R.sup.16,
(q) --(C.sub.1 -C.sub.6)-alkyl!NR.sup.7 R.sup.16,
(r) --NO.sub.2,
(s) --(CH.sub.2).sub.n --SO.sub.2 --N(R.sup.7).sub.2,
(t) --NR.sup.7 CO--(C.sub.1 -C.sub.4)-alkyl,
(u) --CON(R.sup.7).sub.2, or
(v) when R.sup.10 and R.sup.11 are on adjacent carbons, they can join together to form a ring, where R.sup.10 and R.sup.11 are represented by --O--CH.sub.2 --O--;
R.sup.12 is:
(a) H
(b) (C.sub.1 -C.sub.6)-alkyl, unsubstituted or substituted with one or two substituents selected from the group consisting of:
i) --OH,
ii) --O--(C.sub.1 -C.sub.4)-alkyl,
iii) --O--(C.sub.1 -C.sub.4)-cycloalkyl,
iv) --S(O).sub.n --(C.sub.1 -C.sub.4)-alkyl,
iv) --NR.sup.7 --(C.sub.1 -C.sub.4)-alkyl,
v) --N.sup.7 R.sup.16,
vi) --COOR.sup.7,
vii) --CONHR.sup.7,
viii) --OCOR.sup.16,
ix) --CONR.sup.7 R.sup.16,
x) --NR.sup.7 CONR.sup.7 R.sup.16,
xi) --NR.sup.7 COOR.sup.16,
xii) --C(R.sup.6)(OH)--C(R.sup.6)(R.sup.7)(OH), or
xiii) --SO.sub.2 NR.sup.7 R.sup.16,
(c) (C.sub.3 -C.sub.7)-cycloalkyl,
(d) --C(R.sup.6)(OH)--C(R.sup.6)(R.sup.7)(OH),
(e) -perfluoro-(C.sub.1 -C.sub.4)-alkyl,
(f) --OR.sup.7,
(g) --COOR.sup.13,
(h) --COR.sup.16,
(i) --CONR.sup.7 R.sup.16,
(j) --CONHSO.sub.2 R.sup.16 ;
(k) --NO.sub.2,
(l) --NH.sub.2,
(m) --NR.sup.7 R.sup.16,
(n) --NR.sup.7 CONR.sup.7 R.sup.16,
(o) --NR.sup.7 COOR.sup.16,
(p) --NR.sup.7 COR.sup.16,
(q) --NR.sup.7 CONHSO.sub.2 R.sup.16,
(s) --NR.sup.7 SO.sub.2 NH.sub.6,
(t) --NR.sup.7 SO.sub.2 NHR.sup.16,
(u) --NR.sup.7 SO.sub.2 N(R.sup.16).sub.2,
(v) --NR.sup.7 SO.sub.2 NHCOR.sup.16,
(w) --SO.sub.2 NR.sup.7 R.sup.16,
(x) --S(O).sub.2 --NR.sup.7 COR.sup.16,
(y) --S(O).sub.2 --NR.sup.7 COOR.sup.16,
(z) --S(O).sub.2 --NR.sup.7 CONHR.sup.16,
(aa) --S(O).sub.2 --NR.sup.7 CONH.sub.2, or
(ab) --S(O).sub.n --(C.sub.1 -C.sub.4)-alkyl;
Z is:
(a) --CO.sub.2 R.sup.13,
(b) CONH(tetrazol-5-yl),
(c) --CONHSO.sub.2 -phenyl, wherein phenyl is unsubstituted or substituted with one or two substituents selected from the group consisting of:
i) (C.sub.1 -C.sub.4)-alkyl,
ii) --O--(C.sub.1 -C.sub.4)-alkyl,
iii) --CONR.sup.7 R.sup.16,
iv) F, Cl, Br or I,
v) --COOR.sup.7,
vi) (C.sub.1 -C.sub.4)-perfluoroalkyl,
vii) (C.sub.3 -C.sub.7)-cycloalkyl,
viii) NR.sup.7 R.sup.16,
ix) SO.sub.2 NR.sup.7 R.sup.16,
x) hydroxy, or
xi) 2,3-, or 3,4-methylenedioxy;
(d) --CONHSO.sub.2 --(C.sub.1 -C.sub.8)-alkyl, wherein the alkyl group is unsubstituted or substituted with one or two substituents selected from the group consisting of:
i) --OH,
ii) --O--(C.sub.1 -C.sub.4)-alkyl,
iii) --S(O).sub.n --(C.sub.1 -C.sub.4)-alkyl,
iv) --NR.sup.7 --(C.sub.1 -C.sub.4)-alkyl,
v) --NHR.sup.7,
vi) --COOR.sup.7,
vii) --CONHR.sup.7,
viii) --OCOR.sup.16, or
ix) --CONR.sup.7 R.sup.16,
(e) --CONHSO.sub.2 --(C.sub.1 -C.sub.4)-perfluoroalkyl,
(f) --CONHSO.sub.2 --(C.sub.3 -C.sub.7)cycloalkyl,
(g) --CONHSO.sub.2 -heteroaryl, wherein heteroaryl is defined as furyl, unsubstituted or substituted with (C.sub.1 -C.sub.6)-alkyl,
(h) -tetrazol-5-yl,
(i) --CONHSO.sub.2 NH-phenyl, wherein phenyl is unsubstituted or substituted with one or two substituents selected from the group consisting of:
i) (C.sub.1 -C.sub.4)-alkyl,
ii) --O--(C.sub.1 -C.sub.4)-alkyl,
iii) --CONR.sup.7 R.sup.16,
iv) F, Cl, Br or I,
v) --COOR.sup.7,
vi) (C.sub.1 -C.sub.4)-perfluoroalkyl,
vii) (C.sub.3 -C.sub.7)-cycloalkyl,
viii) NR.sup.7 R.sup.16,
ix) SO.sub.2 NR.sup.7 R.sup.16,
x) hydroxy, or
xi) 2,3-, or 3,4-methylenedioxy;
(j) --CONHSO.sub.2 NH--(C.sub.1 -C.sub.8)-alkyl, wherein the alkyl group is unsubstituted or substituted as defined in Z(d),
(k) --CONHSO.sub.2 NH--(C.sub.1 -C.sub.4)-perfluoroalkyl,
(l) --CONHSO.sub.2 NH--(C.sub.3 -C.sub.7)-cycloalkyl,
(m) --CONHSO.sub.2 NH-heteroaryl, wherein heteroaryl is defined as furyl, unsubstituted or substituted with (C.sub.1 -C.sub.6)-alkyl;
(n) --SO.sub.2 NHCO phenyl, wherein phenyl is as defined in Z(c) above,
(o) --SO.sub.2 NHCO--(C.sub.1 -C.sub.8)-alkyl, wherein the alkyl group is unsubstituted or substituted as defined in Z(d),
(p) --SO.sub.2 NHCO--(C.sub.1 -C.sub.4)-perfluoroalkyl,
(q) --SO.sub.2 NHCO-heteroaryl, wherein heteroaryl is as defined in Z(g) above,
(r) --SO.sub.2 NHCON(R.sup.16).sub.2 wherein the R.sup.16 groups are the same or different,
(s) --SO.sub.2 NHCOOR.sup.16,
(t) --PO(OR.sup.7).sub.2, wherein the R.sup.7 groups are the same or different, or
(u) --PO(R.sup.16)OR.sup.7 ;
R.sup.13 is:
(a) H,
(b) (C.sub.1 -C.sub.6)-alkyl,
(c) CHR.sup.14 --O--COR.sup.15,
(d) CH.sub.2 CH.sub.2 --N(C.sub.1 -C.sub.2)-alkyl!.sub.2,
(e) CH.sub.2 CH.sub.2 --NCH.sub.2 CH.sub.2 !.sub.2 O,
(f) (CH.sub.2 CH.sub.2 O).sub.y --O--(C.sub.1 -C.sub.4)-alkyl!, wherein y is 1 or 2,
(g) phenyl, naphthyl, CH.sub.2 -phenyl or CH.sub.2 -naphthyl, where phenyl or naphthyl is substituted or unsubstituted with CO.sub.2 --(C.sub.1 -C.sub.6)-alkyl, ##STR32## R.sup.14 and R.sup.15 independently are (C.sub.1 -C.sub.6)-alkyl or phenyl;
and
R.sup.16 is
(a) --(C.sub.1 -C.sub.6)-alkyl,
(b) --(C.sub.1 -C.sub.4)-perfluoroalkyl,
(c) --(C.sub.1 -C.sub.4)-polyfluoroalkyl,
(d) -phenyl, unsubstituted or substituted with a substituent selected from the group consisting of:
i) (C.sub.1 -C.sub.4)-alkyl,
ii) --O--(C.sub.1 -C.sub.4)-alkyl,
iii) --CONR.sup.7 R.sup.16,
iv) F, Cl, Br or I,
v) --COOR.sup.7,
(e) --(C.sub.1 -C.sub.4)-alkyl-phenyl, wherein the phenyl is unsubstituted or substituted with a substituent selected from the group consisting of:
i) (C.sub.1 -C.sub.4)-alkyl,
ii) --O--(C.sub.1 -C.sub.4)-alkyl,
iii) --CONR.sup.7 R.sup.16,
iv) F, Cl, Br or I,
v) --COOR.sup.7, or
(f) --(C.sub.3 -C.sub.7)-cycloalkyl.

218 more elements

A compound of structural formula III.sub.b :

##STR33## wherein the substituents are as defined in the table below:
______________________________________ R.sup.3 R.sup.8 m R.sup.10 R.sup.11 R.sup.12 Z ______________________________________ H H 1 H H H CO.sub.2 H H H 1 H H H 4-i-Pr- PhenylSO.sub.2 NHCO-- H H 2 H H H CO.sub.2 H H H 2 H H H 4-i-Pr- PhenylSO.sub.2 NHCO-- H H 1 n-Pr H H CO.sub.2 H H H 1 n-Pr H H 4-i-Pr- PhenylSO.sub.2 NHCO-- H H 1 n-Pr n-Pr H CO.sub.2 H H H 1 n-Pr n-Pr H 4-i-Pr- PhenylSO.sub.2 NHCO-- H H 1 H H CO.sub.2 H CO.sub.2 H H H 1 H H CO.sub.2 H 4-i-Pr- PhenylSO.sub.2 NHCO-- H H 1 n-Pr H CO.sub.2 H CO.sub.2 H H H 1 n-Pr H CO.sub.2 H 4-i-Pr- PhenylSO.sub.2 NHCO-- H H 1 n-Pr n-Pr CO.sub.2 H CO.sub.2 H H H 1 n-Pr n-Pr CO.sub.2 H 4-i-Pr- PhenylSO.sub.2 NHCO-- H CH.sub.3 1 H H H CO.sub.2 H H CH.sub.3 1 H H H 4-i-Pr- PhenylSO.sub.2 NHCO-- H CH.sub.3 1 n-Pr H H CO.sub.2 H H CH.sub.3 1 n-Pr H H 4-i-Pr- PhenylSO.sub.2 NHCO-- H CH.sub.3 1 n-Pr n-Pr H CO.sub.2 H H CH.sub.3 1 n-Pr n-Pr H 4-i-Pr- PhenylSO.sub.2 NHCO-- H CH.sub.3 1 H H CO.sub.2 H CO.sub.2 H H CH.sub.3 1 H H CO.sub.2 H 4-i-Pr- PhenylSO.sub.2 NHCO-- H CH.sub.3 1 n-Pr H CO.sub.2 H CO.sub.2 H H CH.sub.3 1 n-Pr H CO.sub.2 H 4-i-Pr- PhenylSO.sub.2 NHCO-- H CH.sub.3 1 n-Pr n-Pr CO.sub.2 H CO.sub.2 H H CH.sub.3 1 n-Pr n-Pr CO.sub.2 H 4-i-Pr- PhenylSO.sub.2 NHCO-- H H 1 n-Pr H CO.sub.2 H PhenylSO.sub.2 NHCO-- H H 1 n-Pr H CO.sub.2 H 4-t-Bu- PhenylSO.sub.2 NHCO-- H H 1 n-Pr H CO.sub.2 H 4-Br- PhenylSO.sub.2 NHCO-- H H 1 n-Pr H CO.sub.2 H 4-CF.sub.3 - PhenylSO.sub.2 NHCO-- H H 1 n-Pr H CO.sub.2 H 2-(CO.sub.2 H)- PhSO.sub.2 NHCO-- H H 1 n-Pr H CO.sub.2 H Tetrazol-5-yl H H 1 n-Pr H CO.sub.2 H Tetrazol-5-ylNHCO-- H H 1 n-Pr H CO.sub.2 H i-PrSO.sub.2 NHCO-- H H 1 n-Pr H CO.sub.2 H CH.sub.3 SO.sub.2 NHCO-- H H 1 H H CF.sub.3 4-i-Pr- PhenylSO.sub.2 NHCO-- H H 1 H H CH.sub.2 OH 4-i-Pr- PhenylSO.sub.2 NHCO-- H H 1 H H OCH.sub.3 4-i-Pr- PhenylSO.sub.2 NHCO-- H H 1 H H Cl 4-i-Pr- PhenylSO.sub.2 NHCO-- H H 1 H H CO.sub.2 CH.sub.3 4-i-Pr- PhenylSO.sub.2 NHCO-- H H 1 n-Pr H CF.sub.3 4-i-Pr- PhenylSO.sub.2 NHCO-- H H 1 n-Pr H CH.sub.2 OH 4-i-Pr- PhenylSO.sub.2 NHCO-- H H 1 n-Pr H OCH.sub.3 4-i-Pr- PhenylSO.sub.2 NHCO-- H H 1 n-Pr H Cl 4-i-Pr- PhenylSO.sub.2 NHCO-- H H 1 n-Pr H CO.sub.2 CH.sub.3 4-i-Pr- PhenylSO.sub.2 NHCO-- H CH.sub.3 1 n-Pr H CF.sub.3 4-i-Pr- PhenylSO.sub.2 NHCO-- H CH.sub.3 1 n-Pr H CH.sub.2 OH 4-i-Pr- PhenylSO.sub.2 NHCO-- H CH.sub.3 1 n-Pr H OCH.sub.3 4-i-Pr- PhenylSO.sub.2 NHCO-- H CH.sub.3 1 n-Pr H Cl 4-i-Pr- PhenylSO.sub.2 NHCO-- H CH.sub.3 1 n-Pr H CO.sub.2 CH.sub.3 4-i-Pr- PhenylSO.sub.2 NHCO-- 5-OCH.sub.3 H 1 n-Pr H CO.sub.2 H 4-i-Pr- PhenylSO.sub.2 NHCO-- 5-OCH.sub.3 H 1 i-Bu H CO.sub.2 H 4-i-Pr- PhenylSO.sub.2 NHCO-- 5-Cl H 1 n-Pr H CO.sub.2 H 4-i-Pr- PhenylSO.sub.2 NHCO-- 5-Cl H i i-Bu H CO.sub.2 H 4-i-Pr- PhenylSO.sub.2 NHCO-- 5-Br H 1 n-Pr H CO.sub.2 H 4-i-Pr- PhenylSO.sub.2 NHCO-- 5-Br H 1 i-Bu H CO.sub.2 H 4-i-Pr- PhenylSO.sub.2 NHCO-- 5-F H 1 n-Pr H CO.sub.2 H 4-i-Pr- PhenylSO.sub.2 NHCO-- 5-F H 1 i-Bu H CO.sub.2 H 4-i-Pr- PhenylSO.sub.2 NHCO-- 5-OCH.sub.3 CH.sub.3 1 n-Pr H CO.sub.2 H 4-i-Pr- PhenylSO.sub.2 NHCO-- 5-OCH.sub.3 CH.sub.3 1 i-Bu H CO.sub.2 H 4-i-Pr- PhenylSO.sub.2 NHCO-- 5-Cl CH.sub.3 1 n-Pr H CO.sub.2 H 4-i-Pr- PhenylSO.sub.2 NHCO-- 5-Cl CH.sub.3 1 i-Bu H CO.sub.2 H 4-i-Pr- PhenylSO.sub.2 NHCO-- H H 1 n-Pr H CO.sub.2 H 4-i-Pr- PhenylCONHSO.sub.2 -- H H 1 n-Pr H CO.sub.2 H 4-t-Pr- PhenylCONHSO.sub.2 -- H H 1 n-Pr H CO.sub.2 H PhenylCONHSO.sub.2 --. ______________________________________

A compound selected from the group consisting of:

N-2-(3,4-methylenedioxyphenyl)-3-phenylpropanoyl!-4-(i-propyl)benzenesulfo namide;
N-2-(3,4-methylenedioxyphenyl)-3-(4-trifluoromethylphenyl)-propanoyl!-4-(i -propyl)benzenesulfonamide;
N-2-(3,4-methylenedioxyphenyl)-3-(4-carbomethoxy-2-propylphenyl)propanoyl! -4-(i-propyl)benzenesulfonamide;
N-2-(3,4-methylenedioxyphenyl)-3-(4-carbomethoxy-2-propylphenyl)propanoyl! -4-(i-propyl)benzenesulfonamide;
N-2-(3,4-methylenedioxyphenyl)-3-(4-carboxy-2-propylphenyl)-propanoyl!-4-( i-propyl)benzenesulfonamide;
N-2-(3,4-methylenedioxyphenyl)-3-(3-methoxyphenyl)propanoyl!-4-(i-propyl)b enzenesulfonamide potassium salt;
N-2-(3,4-methylenedioxyphenyl)-3-(3,5-dimethoxyphenyl)propanoyl!-4-(i-prop yl)benzenesulfonamide potassium salt;
N-2-(3,4-methylenedioxyphenyl)-3-(4-nitrophenyl)propanoyl!-4-(i-propyl)ben zenesulfonamide potassium salt;
N-2-(3,4-methylenedioxyphenyl)-3-(4-aminophenyl)propanoyl!-4-(i-propyl)ben zenesulfonamide trifluoroacetic acid salt;
N-2-(3,4-methylenedioxyphenyl)-3-(2-ethoxyphenyl)propanoyl!-4-(i-propyl)be nzenesulfonamide potassium salt;
N-2-(3,4-methylenedioxyphenyl)-3-(3,4-methylenedioxyphenyl)-propanoyl!-4-( i-propyl)benzenesulfonamide potassium salt;
N-2-(3,4-methylenedioxyphenyl)-3-(3-n-propyloxyphenyl)propanoyl!-4-(i-prop yl)benzenesulfonamide potassium salt;
N-2-(3,4-methylenedioxyphenyl)-3-(4-carbomethoxyphenyl)-propanoyl!-4-(i-pr opyl)benzenesulfonamide
N-2-(3,4-methylenedioxyphenyl)-3-(4-carboxyphenyl)propanoyl!-4-(i-propyl)b enzenesulfonamide dipotassium salt;
N-2-(3,4-methylenedioxyphenyl)-3-(4-(2-carboxylphenyl)phenyl)-propanoyl!-4 -(i-propyl)benzenesulfonamide dipotassium salt;
N-2-(3,4-methylenedioxyphenyl)-3-(4-methylsulfonylphenyl)-propanoyl!-4-(i- propyl)benzenesulfonamide potassium salt;
N-2-(3,4-methylenedioxyphenyl)-3-(2-naphthyl)propanoyl!-4-(i-propyl)benzen esulfonamide potassium salt;
and
N-2-(3,4-methylenedioxyphenyl)-3-(4-hydroxymethyl-2-propylphenyl)propanoyl !-4-(i-propyl)benzenesulfonamide;
N-(4-benzoyl)-1-(3,4-methylenedioxyphenyl)-2-(4-carboxy-2-propylphenyl)eth ane!sulfonamide;
N-(4-(i-propyl)benzoyl)-1-(3,4-methylenedioxyphenyl)-2-(4-carboxy-2-propyl phenyl)ethane!sulfonamide;
and
N-(4-(t-butyl)benzoyl)-1-(3,4-methylenedioxyphenyl)-2-(4-carboxy-2-propylp henyl)ethane!sulfonamide.

20 more elements

Dependencies are inferred from the claim text.

Facts

Application: 08/267,981Filed 7 Jul 1994 · continuation in part
Priority: 20 Jul 1993
Granted: 11 Nov 1997
Term ends: Not estimatedThe source records don’t support an estimate.

Classification17 codes

C07D 317/64
With hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals,…:…
A61P 9/00
Drugs for disorders of the cardiovascular system
A61P 9/08
Drugs for disorders of the cardiovascular system: vasodilators for multiple indications
A61P 9/10
Drugs for disorders of the cardiovascular system: for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary…

Family

Serial95,126Parent of this continuation-in-part · filed 20 Jul 1993
US 5,686,478 AThis patent

From the US filing history. Foreign family members aren’t listed.

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Abstract

A compound of structural Formula I:

##STR31## or a pharmaceutically acceptable salt thereof, wherein:
R.sup.1 and R.sup.2 on adjacent carbon atoms are joined together to form a heterocyclic oxygen containing ring structure containing the following group --O--C(R.sup.6)(R.sup.6)!--O--;
R.sup.3a and R.sup.3b are independently:
(a) H,
(b) F, Cl, Br, or I,
(c) --NO.sub.2,
(d) --NH.sub.2,
(e) --NH(C.sub.1 -C.sub.4)-alkyl,
(f) --N(C.sub.1 -C.sub.4)-alkyl!.sub.2,
(g) --SO.sub.2 NHR.sup.7,
(h) --CF.sub.3,
(i) (C.sub.1 -C.sub.4)-alkyl,
(j) --OR.sup.7,
(k) --S(O).sub.n --(C.sub.1 -C.sub.4)-alkyl,
(l) --NHCO--(C.sub.1 -C.sub.4)-alkyl,
(m) --NHCO--O(C.sub.1 -C.sub.4)-alkyl,
(n) --CH.sub.2 O--(C.sub.1 -C.sub.4)-alkyl,
(o) --O--(CH.sub.2).sub.x --OR.sup.7,
(p) --CONR.sup.7 R.sup.16, or
(q) --COOR.sup.7 ;
m is:
1 or 2;
n is:
0, 1 or 2;
x is:
2, 3 or 4;
R.sup.6 is:
(a) H,
(b) F, or
(c) (C.sub.1 -C.sub.4)-alkyl unsubstituted or substituted with one of the following substituents:
i) --OH,
ii) --NR.sup.7 R.sup.16,
iii) --COOR.sup.7,
iv) --CONHR.sup.7, or
v) --CONR.sup.7 R.sup.6 ;
R.sup.7 is:
(a) H,
(b) (C.sub.1 -C.sub.6)-alkyl,
(c) phenyl;
(d) benzyl, or
(e) (C.sub.3 -C.sub.7)-cycloalkyl;
R.sup.8 is:
(a) H,
(b) (C.sub.1 -C.sub.6)-alkyl, unsubstituted or substituted with a substituent selected from the group consisting of:
i) -phenyl,
ii) --(C.sub.3 -C.sub.7)-cycloalkyl,
iii) --NR.sup.7 R.sup.16,
iv) -morpholin-4-yl,
v) --OH,
vi) --CO.sub.2 R.sup.7, or
vii) --CON(R.sup.7).sub.2,
(c) phenyl, unsubstituted or substituted with a substituent selected from the group consisting of:
i) (C.sub.1 -C.sub.4)-alkyl
ii) --O--(C.sub.1 -C.sub.4)-alkyl
iii) --CONR.sup.7 R.sup.16,
iv) F, Cl, Br or I,
v) --COOR.sup.7, or
vi) 2,3-, or 3,4-methylenedioxy;
R.sup.9 is:
(a) H,
(b) (C.sub.1 -C.sub.6)-alkyl, unsubstituted or substituted with a substituent selected from the group consisting of:
i) -phenyl,
ii) --(C.sub.3 -C.sub.7)-cycloalkyl,
iii) --NR.sup.7 R.sup.16,
iv) --OH,
v) --O--(C.sub.1 -C.sub.4)-alkyl,
vi) --CF.sub.3,
vii) --COOR.sup.7,
viii) --S(O).sub.n --(C.sub.1 -C.sub.4)-alkyl, or
ix) --CON(R.sup.7).sub.2 ;
(c) (C.sub.3 -C.sub.7)-cycloalkyl,
(d) F, Cl, Br, I,
(e) --COOR.sup.7,
(f) --CON(R.sup.7).sub.2,
(g) -perfluoro-(C.sub.1 -C.sub.4)-alkyl,
(h) --O--(CH.sub.2).sub.x --OR.sup.7, or
(i) --S(O).sub.n --(C.sub.1 -C.sub.4)-alkyl;
R.sup.10 and R.sup.11 are independently:
(a) H,
(b) (C.sub.1 -C.sub.6)-alkyl, unsubstituted or substituted with (C.sub.3 -C.sub.7)-cycloalkyl,
(c) (C.sub.2 -C.sub.6)-alkenyl,
(d) (C.sub.2 -C.sub.6)-alkynyl,
(e) Cl, Br, F, I,
(f) (C.sub.1 -C.sub.6)-alkoxy,
(g) when R.sup.10 and R.sup.11 are on adjacent carbons, they can be joined to form a phenyl ring,
(h) perfluoro-(C.sub.1 -C.sub.6)-alkyl,
(i) (C.sub.3 -C.sub.7)-cycloalkyl, unsubstituted or substituted with (C.sub.1 -C.sub.6)-alkyl,
(j) phenyl,
(k) (C.sub.1 -C.sub.6)-alkyl-S(O).sub.n --(CH.sub.2).sub.n --,
(l) hydroxy-(C.sub.1 -C.sub.6)-alkyl,
(m) --CF.sub.3,
(n) --CO.sub.2 R.sup.7,
(o) --OH,
(p) --NR.sup.7 R.sup.16,
(q) --(C.sub.1 -C.sub.6)-alkyl!NR.sup.7 R.sup.16,
(r) --NO.sub.2,
(s) --(CH.sub.2).sub.n --SO.sub.2 --N(R.sup.7).sub.2,
(t) --NR.sup.7 CO--(C.sub.1 -C.sub.4)-alkyl,
(u) --CON(R.sup.7).sub.2, or
(v) when R.sup.10 and R.sup.11 are on adjacent carbons, they can join together to form a ring, where R.sup.10 and R.sup.11 are represented by --O--CH.sub.2 --O--;
R.sup.12 is:
(a) H
(b) (C.sub.1 -C.sub.6)-alkyl, unsubstituted or substituted with one or two substituents selected from the group consisting of:
i) --OH,
ii) --O--(C.sub.1 -C.sub.4)-alkyl,
iii) --O--(C.sub.1 -C.sub.4)-cycloalkyl,
iv) --S(O).sub.n --(C.sub.1 -C.sub.4)-alkyl,
iv) --NR.sup.7 --(C.sub.1 -C.sub.4)-alkyl,
v) --N.sup.7 R.sup.16,
vi) --COOR.sup.7,
vii) --CONHR.sup.7,
viii) --OCOR.sup.16,
ix) --CONR.sup.7 R.sup.16,
x) --NR.sup.7 CONR.sup.7 R.sup.16,
xi) --NR.sup.7 COOR.sup.16,
xii) --C(R.sup.6)(OH)--C(R.sup.6)(R.sup.7)(OH), or
xiii) --SO.sub.2 NR.sup.7 R.sup.16,
(c) (C.sub.3 -C.sub.7)-cycloalkyl,
(d) --C(R.sup.6)(OH)--C(R.sup.6)(R.sup.7)(OH),
(e) -perfluoro-(C.sub.1 -C.sub.4)-alkyl,
(f) --OR.sup.7,
(g) --COOR.sup.13,
(h) --COR.sup.16,
(i) --CONR.sup.7 R.sup.16,
(j) --CONHSO.sub.2 R.sup.16 ;
(k) --NO.sub.2,
(l) --NH.sub.2,
(m) --NR.sup.7 R.sup.16,
(n) --NR.sup.7 CONR.sup.7 R.sup.16,
(o) --NR.sup.7 COOR.sup.16,
(p) --NR.sup.7 COR.sup.16,
(q) --NR.sup.7 CONHSO.sub.2 R.sup.16,
(s) --NR.sup.7 SO.sub.2 NH.sub.6,
(t) --NR.sup.7 SO.sub.2 NHR.sup.16,
(u) --NR.sup.7 SO.sub.2 N(R.sup.16).sub.2,
(v) --NR.sup.7 SO.sub.2 NHCOR.sup.16,
(w) --SO.sub.2 NR.sup.7 R.sup.16,
(x) --S(O).sub.2 --NR.sup.7 COR.sup.16,
(y) --S(O).sub.2 --NR.sup.7 COOR.sup.16,
(z) --S(O).sub.2 --NR.sup.7 CONHR.sup.16,
(aa) --S(O).sub.2 --NR.sup.7 CONH.sub.2, or
(ab) --S(O).sub.n --(C.sub.1 -C.sub.4)-alkyl;
Z is:
(a) --CO.sub.2 R.sup.13,
(b) CONH(tetrazol-5-yl),
(c) --CONHSO.sub.2 -phenyl, wherein phenyl is unsubstituted or substituted with one or two substituents selected from the group consisting of:
i) (C.sub.1 -C.sub.4)-alkyl,
ii) --O--(C.sub.1 -C.sub.4)-alkyl,
iii) --CONR.sup.7 R.sup.16,
iv) F, Cl, Br or I,
v) --COOR.sup.7,
vi) (C.sub.1 -C.sub.4)-perfluoroalkyl,
vii) (C.sub.3 -C.sub.7)-cycloalkyl,
viii) NR.sup.7 R.sup.16,
ix) SO.sub.2 NR.sup.7 R.sup.16,
x) hydroxy, or
xi) 2,3-, or 3,4-methylenedioxy;
(d) --CONHSO.sub.2 --(C.sub.1 -C.sub.8)-alkyl, wherein the alkyl group is unsubstituted or substituted with one or two substituents selected from the group consisting of:
i) --OH,
ii) --O--(C.sub.1 -C.sub.4)-alkyl,
iii) --S(O).sub.n --(C.sub.1 -C.sub.4)-alkyl,
iv) --NR.sup.7 --(C.sub.1 -C.sub.4)-alkyl,
v) --NHR.sup.7,
vi) --COOR.sup.7,
vii) --CONHR.sup.7,
viii) --OCOR.sup.16, or
ix) --CONR.sup.7 R.sup.16,
(e) --CONHSO.sub.2 --(C.sub.1 -C.sub.4)-perfluoroalkyl,
(f) --CONHSO.sub.2 --(C.sub.3 -C.sub.7)cycloalkyl,
(g) --CONHSO.sub.2 -heteroaryl, wherein heteroaryl is defined as furyl, unsubstituted or substituted with (C.sub.1 -C.sub.6)-alkyl,
(h) -tetrazol-5-yl,
(i) --CONHSO.sub.2 NH-phenyl, wherein phenyl is unsubstituted or substituted with one or two substituents selected from the group consisting of:
i) (C.sub.1 -C.sub.4)-alkyl,
ii) --O--(C.sub.1 -C.sub.4)-alkyl,
iii) --CONR.sup.7 R.sup.16,
iv) F, Cl, Br or I,
v) --COOR.sup.7,
vi) (C.sub.1 -C.sub.4)-perfluoroalkyl,
vii) (C.sub.3 -C.sub.7)-cycloalkyl,
viii) NR.sup.7 R.sup.16,
ix) SO.sub.2 NR.sup.7 R.sup.16,
x) hydroxy, or
xi) 2,3-, or 3,4-methylenedioxy;
(j) --CONHSO.sub.2 NH--(C.sub.1 -C.sub.8)-alkyl, wherein the alkyl group is unsubstituted or substituted as defined in Z(d),
(k) --CONHSO.sub.2 NH--(C.sub.1 -C.sub.4)-perfluoroalkyl,
(l) --CONHSO.sub.2 NH--(C.sub.3 -C.sub.7)-cycloalkyl,
(m) --CONHSO.sub.2 NH-heteroaryl, wherein heteroaryl is defined as furyl, unsubstituted or substituted with (C.sub.1 -C.sub.6)-alkyl;
(n) --SO.sub.2 NHCO phenyl, wherein phenyl is as defined in Z(c) above,
(o) --SO.sub.2 NHCO--(C.sub.1 -C.sub.8)-alkyl, wherein the alkyl group is unsubstituted or substituted as defined in Z(d),
(p) --SO.sub.2 NHCO--(C.sub.1 -C.sub.4)-perfluoroalkyl,
(q) --SO.sub.2 NHCO-heteroaryl, wherein heteroaryl is as defined in Z(g) above,
(r) --SO.sub.2 NHCON(R.sup.16).sub.2 wherein the R.sup.16 groups are the same or different,
(s) --SO.sub.2 NHCOOR.sup.16,
(t) --PO(OR.sup.7).sub.2, wherein the R.sup.7 groups are the same or different, or
(u) --PO(R.sup.16)OR.sup.7 ;
R.sup.13 is:
(a) H,
(b) (C.sub.1 -C.sub.6)-alkyl,
(c) CHR.sup.14 --O--COR.sup.15,
(d) CH.sub.2 CH.sub.2 --N(C.sub.1 -C.sub.2)-alkyl!.sub.2,
(e) CH.sub.2 CH.sub.2 --NCH.sub.2 CH.sub.2 !.sub.2 O,
(f) (CH.sub.2 CH.sub.2 O).sub.y --O--(C.sub.1 -C.sub.4)-alkyl!, wherein y is 1 or 2,
(g) phenyl, naphthyl, CH.sub.2 -phenyl or CH.sub.2 -naphthyl, where phenyl or naphthyl is substituted or unsubstituted with CO.sub.2 --(C.sub.1 -C.sub.6)-alkyl, ##STR32## R.sup.14 and R.sup.15 independently are (C.sub.1 -C.sub.6)-alkyl or phenyl;
and
R.sup.16 is
(a) --(C.sub.1 -C.sub.6)-alkyl,
(b) --(C.sub.1 -C.sub.4)-perfluoroalkyl,
(c) --(C.sub.1 -C.sub.4)-polyfluoroalkyl,
(d) -phenyl, unsubstituted or substituted with a substituent selected from the group consisting of:
i) (C.sub.1 -C.sub.4)-alkyl,
ii) --O--(C.sub.1 -C.sub.4)-alkyl,
iii) --CONR.sup.7 R.sup.16,
iv) F, Cl, Br or I,
v) --COOR.sup.7,
(e) --(C.sub.1 -C.sub.4)-alkyl-phenyl, wherein the phenyl is unsubstituted or substituted with a substituent selected from the group consisting of:
i) (C.sub.1 -C.sub.4)-alkyl,
ii) --O--(C.sub.1 -C.sub.4)-alkyl,
iii) --CONR.sup.7 R.sup.16,
iv) F, Cl, Br or I,
v) --COOR.sup.7, or
(f) --(C.sub.3 -C.sub.7)-cycloalkyl.

218 more elements

Facts

Application

08/267,981Filed 7 Jul 1994 · continuation in part

Priority

20 Jul 1993

Granted

11 Nov 1997

Term ends

Not estimatedThe source records don’t support an estimate.

Classification17 codes

C07D 317/64
With hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals,…:…
A61P 9/00
Drugs for disorders of the cardiovascular system
A61P 9/08
Drugs for disorders of the cardiovascular system: vasodilators for multiple indications
A61P 9/10
Drugs for disorders of the cardiovascular system: for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary…